17 beta-hydroxy-17 alpha-methyl-9 (11) androstene-3-one



nited States 2,838,494 Patented June 10, 1958 tice Milton E. Herr,Kalamazoo, Micln, assignor to The Upzglm Company, Kllamazoo,-Mich., acorporation of igan No Drawing. Application September V1'], 1956 SerialNo. 610,414

3 Claims. (Cl. 260-23955) This invention pertains to chemical compoundsof the androstane series and is more particularly concerned withl7fl-hydroxy-17a-methyl-9 1 l -androsten-3-one (*I) and its 9(11)-oxide(II) of the formulae CHI C H:

OH OH OHr 11, CH: Lung,

and

l H I la n which compounds are chemical intermediates, particularly inthe production of the 9a-halo-1 lfl,17p-dihydroxy-17u-methylandrostan-3-one described and claimed in my copendingapplication Serial No. 572,232, filed March 19, 1956, now U. S. PatentNo. 2,806,863, of which the present application is acontinuation-in-part.

The 175 hydroxy 17a methyl 9(11) androsten- 3-one (I) is prepared fromthe known 9(11 )-androstene- 3,17-dione by 3-enamine, suitably thepyrrolidyl 3-enamine, formation followed by alkylation of the17-carbonyl group with methylmagnesiurn halide (or an alkyl lithiumcompound) with subsequent hydrolysis to produce the desired17fl-hydroxy-l7u-methyl-9'( 1 1 -androsten-3- one (I). The9,1l-epoxy-l7fi-hydroxy-Not-methylandrostan3-one (II) is prepared fromcompound I by epoxidation, suitably with perchloric acid andN-bromoacetamide, to produce the corresponding l1-hydroxy-9- bromocompound followed by treatment with base to produce the desired9,1l-epoxy-l7fl-hydroxy-l7u-methylandrostan-3-one (II). Compound 11 canalso be prepared by the method described in application Serial No.572,232. The l7fl-hydroxy-l7e-alkyl-9(ll)-androsten-3- ones and9,1l-epoxy-l7p-hydroxy-l7a-alkylandrostan-3- ones wherein the alkylradical is preferably a lower-alkyl radical containing from two to eightcarbon atoms, e. g., ethyl, propyl, isopropyl, butyl, secondary-butyl,amyl, hexyl, heptyl, octyl, etc., are prepared by the same methods.These compounds are also useful as chemical intermediates, particularlyin the production of the 9ozhalo 11 3,1713 dihydroxy 17a alkylandrostan3 ones of copending application Serial No. 572,232.

The following examples are illustrative of certain preferred productsand processes and are not to be construed as limiting the invention.

EXAMPLE 1 3-!(N-pyrrolidyl)2,9(11 )-andr0stadien-17-0rze To a solutionof 100 milliliters of absolute methanol and eight milliliters of drypyrrolidine is added ten grams of 9(11)-androstene-3,l7-dione. Whilestirring, the mixture is heated to boiling, then cooled to roomtemperature, and finally refrigerated at zero degrees centigrade for twohours. The solid enamine is recovered 2 by filtration, washed with coldmethanol and dried; yield 10.77 grams; melting point 145 to 150 degreescentigrade with decomposition; [al is plus 147 degrees in chloroform. v

Analysis.--Calculated for C H NO: C, 81.35; H, 9.80; N, 4.13. Found: C,81.14; H, 9.77; N, 4.07.

EXAMPLE 2 J-7fl-hydroxy-1 '7-methyl-9 (1 1 )-androsten-3-0ne To astirring mixture of milliliters of 4 molar methyl-magnesium bromide indiethyl ether is added, under nitrogen, a solution of 10.50 grams of3'-(N- pyr'rolidyl)-2,9(1-1) 'androstadien-U-one (III) in 200milliliters of dry tetrahydrofuran during a ten-minute period. Themixture is then warmed and the solvent distilled until the vaportemperature is 62 degrees centigrade- The remaining mixture is heatedunder reflux for nineteen hours and then cooled in an ice-water bath.While stirring, fifty milliliters of water is added dropwise, followedby fifty milliliters of acetic acid and 200 milliliters of methanol. Thesolution then is made basic (pH 9) by the addition of ten percentaqueous sodium hydroxide solution and heated under reflux for fiveminutes. The mixture is made acid (pH 6) by the addition of acetic acidand distilled in vacuo to about 300 milliliters final volume. The solidmaterial which separates is recovered, washed with water, and dried.This material is dissolved in a mixture of 100 milliliters of methylenechloride and 100 milliliters of benzene and passed over a column of 200grams of activated alumina and eluted with (A) 400 milliliters of hexane(Skellysolve B) plus four percent acetone, (B) 400 milliliters ofSkellysolve B plus seven percent acetone, (C) 1000 milliliters ofSkellysolve B plus ten percent acetone, '(D) 1500 milliliters ofSkellysolve B plus 25 percent acetone. Fractions B and first fractionsof C give 0.731 gram of crystalline 9(1l)-androstene-3,l7-dione. Laterfractions of C and first fractions of D give 3.86 grams of the desired17;; hydroxy 17 methyl 9(11) androsten- 3-one which is recrystallizedfrom acetone to yield 2.87 grams of pure product; melting point 196 to198 degrees centigrade.

Analysis.-Calculated for C l-1 0 C, 79.43; H, 10.00, Found: C, 79.53; H,9.96.

EXAMPLE 3 9,1lfl-epoxy-I7,6-hydr0xy-17-methylandrostan-3-0ne 17 3hydroxy 17-methyl 9(11) androsten 3 one (0.50 gram) suspended in twentymilliliters of acetone is treated with ten milliliters of 0.8 'Nperchloric acid and, while stirring in a bath at twenty degreescentigrade, a solution of 250 milligrams of N-bromoacetamide in tenmilliliters of water is added dropwise over a five-minute period. Thebromohydrin separates. After ten minutes, fifty milliliters of water isadded and the product is recovered by filtration, washed with Water anddried; yield 0.333 gram of bromohydrin; melting point 118 to degreescentigrade with decomposition.

This material is dissolved in ten milliliters of ninety percent methanoland titrated with N/l0 aqueous sodium hydroxide solution until themixture is pink to phenolphthalein. The mixture is diluted with twentymilliliters of water and the separated 9,11/3-epoxy-175-hydroxy-17-methylandrostan-3-one recovered by filtration, dried, andrecrystallized from acetone; melting point 205 to 207 degreescentigrade.

EXAMPLE 4 9,1 Ifl-epoxy-J 7fl-hydroxy-17-methylandrostan-3-one percentethanol is treated with 100 milligrams of five percent palladium oncharcoal and shaken with hydrogen for 7 /2 minutes, the hydrogenpressure being about thirty pounds per square inch. The catalyst isremoved by filtration and the filtrate concentrated to dryness in vacuo.on a hot water bath. The residue is dissolved in benzene and heptane(Skellysolve C) added. There is obtained 0.215 gram of9,1lfl-epoxy-17,8-hydroxy-17a-methyl androstan-3-one; melting point 195to 202 degrees centigrade. Recrystallized from acetone it melted at 206to 210 degrees centigrade; [M plus eight degrees in ethanol.

Analysis.-Calculated for C H O C, 75.44; H, 9.50. Found: C, 75.76; H,9.90.

I claim:

1. A compound selected from the group consisting of17B-hydroxy-17a-methyl-9 1 1 )-androsten-3-one and 9,1 1- epoxy-17B-hydroxy-17a-methylandrostan-3-one.

2,838,494 I w a a 2. 17fl-hydroxy-l7a-methyl-9( 1 1)-androsten-3-one. 3.9,1l-epoxy-17B-hydro1ry-17a-methylandrostan-3-one.

References Cited in the file of this patent UNITED STATES PATENTS OTHERREFERENCES Klein et al., Chem. Abst., v01. 49, page 2596 (1955),

citing Ca-sopis Lekaru Ceskych 93,'pages 371-383 (1954).

Luoschez, Chem. Abst., vol. 49, page 13457 (1955), citing Pediatrics 15,pp. 537-42 (1955).

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF17B-HYDROXY-17A-METHYL-9(11)-ANDROSTEN-3-ONE AND9,11EPOXY-17B-HYDROXY-17A-METHYLANDROSTAN-3-ONE.